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Originally published as JCO Early Release 10.1200/JCO.2008.18.7120 on October 20 2008 © 2008 American Society of Clinical Oncology.
Clinical Relevance of "Late" in the Management of Late Relapse After Treatment for a Germ Cell Tumor
Department of Medical Oncology, Peter MacCallum Cancer Center, University of Melbourne, Melbourne, Australia Dramatic improvements in treatment for germ cell tumors occurred in the late 1970s with the introduction of cisplatin-based combination chemotherapy. For the first time, cure was achievable for the majority of patients treated for metastatic disease.1 As a medical oncology trainee in the mid-1980s, I was taught the prevailing dogma that relapses virtually never occurred more than 2 years after completion of this chemotherapy. However, as early as 1983, reports began to emerge of "late" relapses after cisplatin-based combination chemotherapy.2 By the mid-1990s, investigators at Indiana University reported 81 cases of late relapse, including 34 patients experiencing relapse 2 to 5 years after treatment and 47 patients experiencing relapse more than 5 years after treatment.3 The authors concluded that late relapse was associated with relative resistance to chemotherapy, and surgery was recommended as the preferred mode of therapy. There have been multiple subsequent publications reporting experience with late relapse, mostly single-institution series from large referral centers. Interpretation of these reports is difficult because of variability of the cases considered with respect to prior therapy, histologic group, stage at initial diagnosis, primary site, and inclusion of cases with prior relapse. A recent comprehensive review of published literature concluded that the risk of late relapse was 3.2% in nonseminoma and 1.2% in seminoma.4 The accepted definition of late relapse was relapse beyond 2 years after completing therapy or after achieving complete response, in the absence of a new primary tumor. The most common site of relapse was the retroperitoneum in both seminoma and nonseminoma. In this issue of Journal of Clinical Oncology, Sharp et al5 report the single-institution experience of late relapse at Memorial Sloan-Kettering Cancer Center (New York, NY), analyzing prognostic factors for cancer-specific survival (CSS). As with many prior series, they have included chemotherapy-naive patients experiencing relapse after orchiectomy followed by surveillance, retroperitoneal lymph node dissection, or radiation therapy. They report 75 cases of late relapse, comprising 70 patients with nonseminoma and five patients with pure seminoma. The time to relapse was 2 to 5 years in 28 patients (38%), 5 to 10 years in 19 patients (26%), and more than 10 years in 27 patients (36%). Eighteen patients (24%) had not received any chemotherapy at the time of relapse. The 5-year CSS was 93% in chemotherapy-naive patients but only 49% in those who had received prior chemotherapy. Complete resection of disease at relapse was associated with improved CSS. In multivariate analyses, considering only those who had received prior chemotherapy, the presence of symptoms and multifocal disease at relapse were each associated with an inferior CSS. The authors state "complete surgical resection is central to the management of late relapse" but qualify this elsewhere with the statement "we believe that the definition of late relapse should be limited to patients who have had prior chemotherapy... . "5 Interpretation of the available literature can be confusing, particularly for the casual reader. This is demonstrated by the latter quote, which contradicts the definition of late relapse used throughout the article. Many reports discussing late relapse emphasize the value of complete surgical resection (and salvage chemotherapy) but include chemotherapy-naive cases such as stage I nonseminoma managed with surveillance. There is a lack of clear data to indicate whether chemotherapy-naive patients who experience relapse more than 2 years after radiation therapy, retroperitoneal lymph node dissection, or management with a surveillance strategy need to be managed in a different way than similar patients experiencing relapse within the first 2 years. Early-stage seminoma can be managed with radiation therapy, surveillance, or single-agent carboplatin chemotherapy. After radiation therapy or surveillance, the interval to relapse has not been shown to affect outcome or influence management at relapse. Although follow-up is still relatively brief regarding the management of stage I seminoma with carboplatin,6,7 the available data do not indicate that time to relapse should alter subsequent management. The situation is less clear in patients with early-stage, chemotherapy-naive nonseminoma who experience late relapse. These patients may have been managed with a surveillance strategy after orchiectomy for stage I disease or with retroperitoneal lymph node dissection for stage I or II disease. George at al8 reported that only four of 10 chemotherapy-naive patients achieved a complete response with chemotherapy alone after late relapse, but Sharp et al5 report a 93% 5-year CSS rate in 18 similar cases. In these cases, a 2-year cutoff to define late relapse may not be appropriate. Personally, I would manage a patient experiencing relapse 30 months into surveillance for stage I nonseminoma in the same way as one experiencing relapse after 18 months. In contrast, in a patient experiencing relapse after 8 years of surveillance, I would have a low threshold for surgery as part of management. The most important observation regarding late relapse in patients who have received cisplatin-based combination chemotherapy is that surgical resection of all recurrent disease is important in determining outcome. This is due to relative resistance to chemotherapy, but also due to the frequency of teratoma within the recurrence. Complete resection should be part of the management plan, whenever feasible, either before or after salvage chemotherapy. In cases with completely resected teratoma as the only recurrence, surgery alone may be adequate. Not surprisingly, patients with multiple sites or extensive late recurrence are often not able to undergo potentially curative resections and do less well. We know that initial therapy of poor-prognosis cases at a center that treats a large number of similar cases results in improved survival.9 It is almost certain that the same is true for these cases of late relapse, and referral to a center with highly specialized surgical expertise is essential for optimal care. The mechanism of resistance to chemotherapy remains unknown. In late relapse cases, an increased frequency of teratomatous elements in the primary tumor, postchemotherapy resected masses, or at relapse has been reported, suggesting a possible relationship between teratoma and late relapse.5 Somatic transformation of teratoma to other histologic malignancies, such as sarcomas and adenocarcinomas, is also more frequent in cases of late relapse compared with resections performed as part of initial therapy. These observations have prompted the hypothesis that late relapse may be the result of transformation within teratoma persisting after chemotherapy but remaining dormant for years before transformation.10 If this is the explanation, it has potential implications for management of the retroperitoneum, both in early-stage and postchemotherapy nonseminoma. It also implies that pure seminoma relapsing more than 2 years after cisplatin-based combination chemotherapy might not be as chemotherapy-resistant as cases of relapsed nonseminoma. The available data are inadequate to test the latter hypothesis, because the number of cases of relapsed seminoma is small. Many questions remain unanswered. What is the mechanism of resistance to chemotherapy? Do chemotherapy-naive patients who experience relapse more than 2 or more than 5 years after therapy also demonstrate resistance to chemotherapy? Is a 2-year cutoff the most appropriate to define late relapse after cisplatin-based combination chemotherapy? Is seminoma relapsing late after cisplatin-based chemotherapy also resistant to salvage chemotherapy? Do patients with stage I seminoma experiencing relapse after adjuvant carboplatin demonstrate more resistance to chemotherapy than those experiencing relapse during surveillance or after radiation therapy? What are the optimal strategies for long-term follow-up after treatment for a germ cell tumor, balancing the need to detect late relapse when it is resectable with the risks of exposure to diagnostic radiation? Uncertainties about the latter question have contributed to widely divergent recommendations and clinical practice in follow-up after initial management of germ cell tumors.11,12 How might we answer some of these questions? The broad definition of late relapse used commonly in earlier reports and in the article by Sharp et al5 is confusing and should no longer be used. Future reports should separately analyze cohorts according to prior therapy and histology. With respect to new treatment approaches for stage I seminoma, we should not make the same mistake as we did in the 1980s and declare that we have nothing more to learn about late relapses. Initial management of germ cell tumors has benefited greatly from pooling of international data sets13 and international consensus.14 It is time to consider the same approaches, both to better understand and manage late relapse and also to develop useful and internationally consistent guidelines for follow-up. AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author indicated no potential conflicts of interest. NOTES published online ahead of print at www.jco.org on October 20, 2008 REFERENCES
1. Einhorn LH: Testicular cancer as a model for a curable neoplasm: The Richard and Hinda Rosenthal Foundation Award Lecture. Cancer Res 41:3275-3280, 1981 2. Terebelo HR, Taylor HG, Brown A, et al: Late relapse of testicular cancer. J Clin Oncol 1:566-571, 1983[Medline] 3. Baniel J, Foster RS, Gonin R, et al: Late relapse of testicular cancer. J Clin Oncol 13:1170-1176, 1995[Abstract] 4. Oldenburg J, Martin JM, Fossa SD: Late relapses of germ cell malignancies: Incidence, management, and prognosis. J Clin Oncol 24:5503-5511, 2006 5. Sharp DS, Carver BS, Eggener SE, et al: Clinical outcome and predictors of survival in late relapse of germ cell tumor. J Clin Oncol doi:10.1200/JCO.2007.15.7453 [epub ahead of print on October 20, 2008] 6. Oliver RT, Mason MD, Mead GM, et al: Radiotherapy versus single-dose carboplatin in adjuvant treatment of stage I seminoma: A randomised trial. Lancet 366:293-300, 2005[CrossRef][Medline] 7. Oliver RT, Mead GM, Fogarty PJ, et al: Radiotherapy versus carboplatin for stage I seminoma: Updated analysis of the MRC/EORTC randomized trial (ISRCTN27163214). J Clin Oncol 26:5s, 2008 (suppl; abstr 1)[CrossRef] 8. George DW, Foster RS, Hromas RA, et al: Update on late relapse of germ cell tumor: A clinical and molecular analysis. J Clin Oncol 21:113-122, 2003 9. Collette L, Sylvester RJ, Stenning SP, et al: Impact of the treating institution on survival of patients with "poor-prognosis" metastatic nonseminoma: European Organization for Research and Treatment of Cancer Genito-Urinary Tract Cancer Collaborative Group and the Medical Research Council Testicular Cancer Working Party. J Natl Cancer Inst 91:839-846, 1999 10. Pezaro CJ, Mallesara G, Toner GC. Late-relapsing stage 1 nonseminoma. J Clin Oncol doi:10.1200/JCO.2008.19.3417 [epub ahead of print on November 3, 2008] 11. National Comprehensive Cancer Network: Testicular Cancer Clinical Practice Guidelines in Oncology (version 2.2008). National Comprehensive Cancer Network, 2006. Available at: http://www.nccn.org/professionals/physician_gls/PDF/testicular.pdf 12. van As NJ, Gilbert DC, Money-Kyrle J, et al: Evidence-based pragmatic guidelines for the follow-up of testicular cancer: Optimising the detection of relapse. Br J Cancer 98:1894-1902, 2008[CrossRef][Medline] 13. Steyerberg EW, Keizer HJ, Fossa SD, et al: Prediction of residual retroperitoneal mass histology after chemotherapy for metastatic nonseminomatous germ cell tumor: Multivariate analysis of individual patient data from six study groups. J Clin Oncol 13:1177-1187, 1995[Abstract] 14. International Germ Cell Consensus Classification: A prognostic factor-based staging system for metastatic germ cell cancers. J Clin Oncol 15:594-603, 1997
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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